The human intestinal microbiome includes viruses that replicate in eukaryotic cells, plants, fungi or bacteria. However, very little is known on how viral recognition shapes mucosal immune responses. Furthermore, a detailed understanding of the signaling intermediates that confer the sensing of viruses for induction of type I interferons s critical for strategies to curtail viral mechanisms that impede innate immune defenses. Our work identified the guanine nucleotide exchange factor H1 (GEF-H1), encoded by the arhgef2 gene, as a central component of host defense activation during viral infections. We hypothesize that GEF-H1 serves as a gatekeeper for innate host defenses by controlling interferon response factor activation, which is part of signaling pathways induced by recognition of bacteria and viruses. Defining the functional role of this newly discovered central component of microbial pattern recognition should provide pivotal insights into the integration of antiviral host defenses into immune activation pathways that control the microbiota in the intestine.